ES2224421T3 - USE OF CHOLINESTERASE INHIBITORS TO COMBAT LACK OF ATTENTION DISORDERS. - Google Patents

Abstract

The invention provides the use of cholinesterase inhibitors, particularly acetylcholinesterase inhibitors such as galantamine, in the manufacture of a medicament for combatting attention deficit disorders.

Description

Use of cholinesterase inhibitors to combat inattention disorders

The present invention relates to the fight against inattention disorders (so called abbreviated hereinafter ADD). In particular, the invention is refers to the use of certain cholinesterase inhibitors pharmaceutically acceptable in the manufacture of a medicine intended to be used to combat disorders of lack of Attention.

Inattention disorders affect children, adolescents and adults, affecting up to 10% of children and at least 2% of adults. The condition in childhood is He often knows her as a lack of attention disorder with hyperactivity (ADHD). Symptoms are usually manifested by First time between 2 and 5 years old. These children present a short duration of the attention period and motor hyperactivity, and they are messy, forgetful and impulsive. Lack disorder of attention with hyperactivity can have serious effects on the progress and academic performance of the child and causes stress to the family and teachers and difficulties in the child's interaction with peer group members. The condition can persist prolonging to adulthood. In adults, main symptoms include distractibility, disorganization and accident proneness. The condition in adults and children it causes serious disorders of normal lifestyle patterns and creates great tensions in all aspects of everyday life both at home and in the workplace and in relationships social. In the sense in which it is used herein, the expression "carelessness disorder" includes the forms both adults and children of the condition, as well as hyperkinetic disorders and disorders that include any of the criteria that characterize the Classification DSM-IV of disorders according to the Association American Psychiatric

Several therapies have been proposed, but they have not proved satisfactory, due, inter alia , to their lack of efficacy and / or to their undesirable side effects. They have been used clinically in the treatment of stimulatory disorders such as dexamphetamine, methylphenidate and pemoline. Although these stimulants have been shown to improve primary manifestations such as motor activity, distractibility and impulsivity in some patients, their usefulness is limited by their side effects, including anorexia, delayed conciliation of the Sleep, mood swings and exacerbation of pre-existing psychotic symptoms, along with the potential for abuse. Other classes of drugs such as tricyclic antidepressants have been suggested in the literature, but they are not generally considered to be effective agents for the treatment of inattention disorder.

WO-A-92 20328 describes the use of cholinesterase inhibitors, including galantamine, to counteract sedative side effects, hypnotic or respiratory-depressive benzodiazepines when benzodiazepines are used to treat certain diseases, such as hyperactivity in children.

JL Juncos et al ., Neurology, 1997, 48 , page A397, indicate improvements in certain symptoms of inattention disorder in a tacrine test in patients suffering from Tourette Syndrome, and suggest the use of tacrine as an alternative to agents Dopamine blockers to treat Tourette syndrome.

WO-A-95 29909 describes certain amide compounds to increase the release of neurotransmitters such as acetylcholine, dopamine and serotonin, and suggests its use in the treatment of diseases liable to be treated based on increasing the release of acetylcholine, dopamine or serotonin, as is the case for example inattention disorder

EP-A-0 229 391 describes certain piperidine derivatives that have activity against cholinesterase, and suggests its use as medicines on the basis of this activity, for example for the treatment of attention disorders

EP-A-0 411 534 describes certain tacrine derivatives and suggests their use in treatment of cerebral insufficiency states characterized by decreased production or release of cerebral acetylcholine, as is the case with hyperkinesia, for example.

EP-A-0 607 864 describes tricyclic compounds that have inhibitory activity of acetylcholinesterase, and suggests its use in the treatment of cholinesterase dependent diseases, such as hyperkinesia

There is therefore a need for a new therapeutic treatment for the therapeutic management of disorders of lack of attention. The present invention provides such treatment.

Thus, we have surprisingly discovered that cholinesterase inhibitors such as galantamine can Effectively combat carelessness disorder.

According to one aspect, the present invention provides a method that is to combat attentionlessness disorder and comprises the operation of administering to a subject an inhibitor of Pharmaceutically acceptable cholinesterase.

Consequently, the invention provides the use of a pharmaceutically acceptable galantamine compound of formula I or II in the manufacture of a medicine to combat the disorder of lack of attention.

In the sense in which it is used in the present, the word "combat" includes both therapy and Prophylaxis

The invention includes the use of any inhibitor of cholinesterase of formula I or II, naturally provided that the same be pharmaceutically acceptable.

Examples of cholinesterase inhibitors which can be used according to the invention include prodrugs in the which inhibitor is modified according to the principles of preparation of prodrugs that are known in the art. The Examples of such modifications include the introduction of groups hydrophilic and lipophilic to increase solubility or penetration through cell membranes, respectively.

They are preferred to be used according to the invention. acetylcholinesterase inhibitors of formula I or II, and particularly those who are able to cross the barrier blood brain

Cholinesterase inhibitors of formula I or II that are particularly preferred to be used according to the invention include galantamine, epigalantamine and the norgalantamine and analogues, salts and derivatives of any of these. Galantamine was previously known as "galanthamine." It is a tertiary alkaloid that can be extracted from several winter bell bulbs, and p. ex. from the bell of Caucasian winter galanthus woronowii (Amaryllidaceae) and de related species and daffodil bulbs, or it can be done by chemical synthesis This inhibitor has a high selectivity for with acetylcholinesterase, as opposed to butyrylcholinesterase. This inhibitor is considerably selectively active in nicotinic receptor sites, exerting very little effect on muscarinic receptor sites.

Cholinesterase inhibitors that are suitable to be used in the invention are galantamine and its derivatives of formula (I):

one

in which the dashed line represents a double bond optionally present between atoms of carbon 3 and 4, each R1 is independently selected from among the members of the group consisting of hydrogen, hydroxyl, straight or branched chain alkyl, hydroxyalkyl, carboxyalkylamino, alkylamino, acyl, lower alkanoyl, cyano, sulfhydryl, C 1-6 alkoxy, alkylthio, aryloxy, arylthio, aryloxy R 3 -substituted, arylthio R 3 -substituted, aralkoxy, a group aryl or aliphatic carbamyl optionally R 3 -substituted, aralkylthio, aralkoxy R 3 -substituted, aralkylthio R 3 -substituted, aryloxymethyl, aryloxymethyl R 3 -substituted, alkanoyloxy, alkanoyloxy hydroxy-substituted, benzoyloxy, benzoyloxy R 3 -substituted, aryloxycarbonyl and aryloxycarbonyl R_ {3} -replaced,

R_ {2} is selected from among the members of the group consisting of hydrogen, C 1-6 alkyl straight or branched chain, an alkenyl or alkaryl group, optionally substituted by a halogen atom or a cycloalkyl, hydroxy, alkoxy, nitro, amino, aminoalkyl, acylamino, heteroaryl, heteroaryl-alkyl, aryl, arylalkyl, cyano, amyl, aroyl, cycloalkylmethyl, allyl, phenyl, phenyl R 3 -substituted, alkylphenyl, alkylphenyl R 3 -substituted, heterocyclyl selected from among the members of the group consisting of α- or β-furyl, α- or β-thienyl, tenyl, pyridyl, pyrazinyl and pyrimidyl, alkyl-heterocyclyl or heterocyclyl R'-substituted, where R 'is alkyl or alkoxy,

each R 3 is independently selected from among the members of the group consisting of hydrogen, hydroxyl, sulfhydryl, alkyl, hydroxyalkyl, aryl, aralkyl, alkoxy, mercaptoalkyl, aryloxy, thiaryloxy, alkaryloxy, mercaptoalkyl, nitro, amino, N-alkylamino, N-arylamino, N-alkarylamino, fluoro, chlorine, bromine, iodine and trifluoromethyl,

each R4 is independently selected from among the members of the group consisting of hydrogen, halo, trifluoromethyl or C 1-4 alkyl,

each R5 is independently selected among the members of the group consisting of hydrogen or hydroxymethyl,

R 6 is hydrogen or alkyl of C 1-6, or when R 1 on carbon atom 2 is hydroxyl, R 6 can be a half of formula I in which R 6 is hydrogen and R 1 is a bridge bond; or

R 1 on carbon atom 2 and R 6 can form semicarbazone together,

X is oxygen or NR3,

And it's nitrogen or phosphorus,

and methylenedioxides thereof and salts of Acid addition thereof pharmaceutically acceptable.

Of the compounds of formula I which may be used in the method of the invention, are preferred compounds those in which the alkyl halves contain 1 to 8 atoms carbon, halogen atoms are preferably fluorine, bromine and chlorine, the aryl halves are preferably phenyl, the groups cycloalkyl are preferably rings of 3 to 7 members, and in Special cyclopropyl or cyclobutyl, acyl groups are preferably lower alkanoyl groups, and halves heteroaryl are preferably 5 to 8 member rings, such as p. ex. thienyl, furyl, pyridyl, pyrrolyl or pyrizanyl.

Preferred compounds of formula I are those compounds of formula II

2

wherein R1 and R2, which they can be the same or different, each one represents an atom of hydrogen or an acyl group, such as a lower alkanoyl group, as p. ex. an acetyl group or a straight chain aryl group or branched, as p. ex. methyl, ethyl, propyl or isopropyl;

R 3 is an alkyl, alkenyl or alkaryl group straight or branched chain that is optionally substituted by a halogen atom or a cycloalkyl, hydroxy, alkoxy group, nitro, amino, aminoalkyl, acylamino, heteroaryl, heteroarylalkyl, aroyl, aroylalkyl or cyano; Y

R 4 represents a hydrogen atom or of halogen attached to at least one of the cyclic carbons of the skeleton tetracyclic;

and pharmaceutically acceptable salts of themselves, such as those consisting of hydrobromide, hydrochloride, methylsulfate or metaiodide.

Formula II includes its own galantamine

The own ones are particularly preferred galantamine and salts thereof such as halides, as per example galantamine hydrobromide, and the use of these compounds in the manufacture of a medicine to combat the disorder of lack of attention provides an additional aspect of the invention.

Among these compounds are those described in EP-A-236684 and WO88 / 08708, whose descriptions are hereby incorporated by reference. Galantamine and its derivatives of formula I and II can be prepared by the methods described in these publications.

Cholinesterase inhibitors of formula I or II that are suitable for use in the invention include compounds that are functionally similar to galantamine. These are defined herein as compounds that possess at least 10 times higher selectivity, preferably at least 20 times higher selectivity, more preferably at least 40 times higher selectivity, and most preferably at least 50 times higher selectivity, for acetylcholinesterase compared to butyrylcholinesterase, as measured by the in vitro method of Thomsen and Kewitz: Selective Inhibition of Human Acetylcholinesterase by Galantamine in vitro and in vivo , Life Sciences, Vol. 46, pp. 1553-1558 (1990), and of T. Thomsen, H. Kewitz and O. Pleul, J. Clin. Chem. Clin. Biochem 26 469-475 (1988). The in vitro assay described by Thomsen and Kewitz in Life Sciences, Vol. 46, pp. 1553-1558 (1990) is the one referred to here when done numerically (10 times higher, 20 times higher, 40 times higher) referring to the selectivity towards acetylcholinesterase compared to butyrylcholinesterase. According to Thomsen and Kewitz, galantamine hydrobromide, when tested under the conditions described, has a selectivity 50 times higher; and this selectivity value is taken as the "fixed point" provided that here it is about in vitro selectivities, and could be used, in order to determine the selectivities for other cholinesterase inhibitors of formula I or II, as the value calibration which is established with galantamine hydrobromide in any repetition of the experiment described by Thomsen and Kewitz. Thus, with reference to this method of determination, a preferred acetylcholinesterase inhibitor is one that in the described in vitro method has a selectivity at least 10 times higher with acetylcholinesterase compared to butyrylcholinesterase, such as a selectivity at least 20 times higher for acetylcholinesterase compared to butyrylcholinesterase, and p. ex. a selectivity at least 40 times higher for acetylcholinesterase compared to butyrylcholinesterase. A selectivity test (from Sigma Diagnostics) is commercially available.

To be used in the invention, the inhibitor of cholinesterase such as galantamine and derivatives and salts of the same can be formed according to conventional pharmacy methods, together with, when appropriate, one or more vehicles, pharmaceutically acceptable excipients or diluents such as which are for example described in Remingtons Pharmaceutical Sciences. Such formulations may for example take the form of tablets, capsules, solutions, or troches, pessaries, creams, suppositories or transdermal formulations such as patches, creams, ointments or lotions, depending on the route of administration to use, which may include the enteral route or the route parenteral, including oral or route injection intravenous, intramuscular or subcutaneous, or the intrathecal route by means of an implanted device.

Routes of oral administration and transdermal

The specific regimes and amounts of dosage will depend on the individual patient and may be determined by the doctor based on the circumstances individual. For oral administration, the doses may be located within the range of amounts of 5-100 mg per day, such as 2 to 70 mg per day, and p. ex. 10 to 30 mg For Transdermal administration Galantamine can be supplied in equivalent daily doses. For parenteral administration the Dosages may be located within the range quantities of 0.1 to 100 mg per day, and may consist of such dosages such as 5 to 100 mg per day, and p. ex. 10 to 50 mg per day, including dosages such as 5 to 30 mg per day; lower dosages are often preferred.

Galantamine and its acid addition salts They form crystals. Such compounds are generally only sparingly soluble in water at room temperature; being by consequently injectable compositions normally in the form of an aqueous suspension If necessary, adjuvants can be used to the pharmaceutically acceptable suspension. Typically, a Suspension of this type will be used at a concentration of 0.1-50 mg / ml, such as a concentration of 1-50 mg / ml, most commonly 5-40 mg / ml, and for example 5-30 mg / ml or of 10-40 mg / ml, such as a concentration of 10-30 mg / ml, and especially of 20-30 mg / ml galantamine.

Cholinesterase inhibitors such as galantamine and salts thereof can be used as a drug unique in the treatment of inattention disorder, or they can be used together with other useful agents to treat the inattention disorder

The invention is described below by making reference to the following non-limiting examples.

Example 1 Formation of tablets containing galantamine Composition of 1 tablet containing 1 mg of galantamine

Hydrobromide galantamine 0.001 g Phosphate calcic 0.032 g Lactose 0.005 g Starch wheat 0.0056 g Cellulose microcrystalline 0.015 g talcum powder 0.0007 g Stearate magnesium 0.0007 g

Composition of 1 tablet containing 5 mg of galantamine

Hydrobromide galantamine 0.005 g Phosphate calcic 0.024 g Lactose 0.004 g Starch wheat 0.004 g Cellulose microcrystalline 0.04 g talcum powder 0.002 g Stearate magnesium 0.001 g

Composition of 1 tablet containing 10 mg of galantamine

Hydrobromide galantamine 0.010 g Lactose 0.040 g Starch wheat 0.0234 g Cellulose microcrystalline 0.0374 g talcum powder 0.0036 g Stearate from magnesium 0.0012 g Jelly 0.0044 g

Preparation

All tablets are prepared according to Routine procedures to make tablets.

Example 2 Treatment of patients suffering from lack of Attention

Three patients from 9 to 11 years of age who had been diagnosed as having a lack of attention disorder were treated with 5 mg of galantamine given 3 times a day for a total of 14 days. After this period of time had elapsed, the patients presented a marked improvement in symptoms, particularly with regard to attention and continuous agitation, according to prosecution on an ecological behavioral scale (translated: Barkley, RA et al ., Assessment of situational variation in the problematic behaviors of children: The Questionnaires on Situations at Home and at School, in RJ Prinz (Ed), Advances in Behavioural Assessment of Children and Families, vol. 3, pp. 157-176, Greenwick, CT, JAI Press, Inc.).

Those of an additional cohort of two patients of 5 years old with inattentive disorder have been treated and again the symptoms have improved overall, especially related to attention, as measured by the ANT (ANT = Amsterdam Neuropsychological Tests), which are tests standard that measure reaction times for different chores.

In this case, the protocol is firstly a realization of the tests as a baseline before the medication and a new realization of the tests after 2 days of medication, and then after a week a repetition of the tests. Ecological scales were also used before and they are now being evaluated after one week, after two weeks, etc. for a month-long treatment. The following table presents a selection of results obtained for these two children before and after treatment with galanta-
mine.

3

These data were normalized and subjected to error analysis that showed an improvement in the attention (reduction of time (msec.) to conclude certain tasks and with fewer errors) of more than 2.5 standard deviations after medication with galantamine hydrobromide at a rate of 2.5 mg 3 times a day.

Claims (5)

1. Use of galantamine or a derivative thereof of formula I: 4 in which the dashed line represents a double bond optionally present between atoms of carbon 3 and 4, each R1 is independently selected from among the members of the group consisting of hydrogen, hydroxyl, straight or branched chain alkyl, hydroxyalkyl, carboxyalkylamino, alkylamino, acyl, lower alkanoyl, cyano, sulfhydryl, C 1-6 alkoxy, alkylthio, aryloxy, arylthio, aryloxy R 3 -substituted, arylthio R 3 -substituted, aralkoxy, a group aryl or aliphatic carbamyl optionally R 3 -substituted, aralkylthio, aralkoxy R 3 -substituted, aralkylthio R 3 -substituted, aryloxymethyl, aryloxymethyl R 3 -substituted, alkanoyloxy, alkanoyloxy hydroxy-substituted, benzoyloxy, benzoyloxy R 3 -substituted, aryloxycarbonyl and aryloxycarbonyl R_ {3} -replaced, R_ {2} is selected from among the members of the group consisting of hydrogen, C 1-6 alkyl straight or branched chain, an alkenyl or alkaryl group, optionally substituted by a halogen atom or a cycloalkyl, hydroxy, alkoxy, nitro, amino, aminoalkyl, acylamino, heteroaryl, heteroaryl-alkyl, aryl, arylalkyl, cyano, amyl, aroyl, cycloalkylmethyl, allyl, phenyl, phenyl R 3 -substituted, alkylphenyl, alkylphenyl R 3 -substituted, heterocyclyl selected from among the members of the group consisting of α- or β-furyl, α- or β-thienyl, tenyl, pyridyl, pyrazinyl and pyrimidyl, alkyl-heterocyclyl or heterocyclyl R'-substituted, where R 'is alkyl or alkoxy, each R 3 is independently selected from among the members of the group consisting of hydrogen, hydroxyl, sulfhydryl, alkyl, hydroxyalkyl, aryl, aralkyl, alkoxy, mercaptoalkyl, aryloxy, thiaryloxy, alkaryloxy, mercaptoalkyl, nitro, amino, N-alkylamino, N-arylamino, N-alkarylamino, fluoro, chlorine, bromine, iodine and trifluoromethyl, each R4 is independently selected from among the members of the group consisting of hydrogen, halo, trifluoromethyl or C 1-4 alkyl, each R5 is independently selected among the members of the group consisting of hydrogen or hydroxymethyl, R 6 is hydrogen or alkyl of C 1-6, or when R 1 on carbon atom 2 is hydroxyl, R 6 can be a half of formula I in which R 6 is hydrogen and R 1 is a bridge bond; or R 1 on carbon atom 2 and R 6 can form semicarbazone together, X is oxygen or NR3, And it's nitrogen or phosphorus, and methylenedioxides thereof and salts of acid addition thereof pharmaceutically acceptable in the manufacture of a medicine to combat inattention disorders 2. Use of galantamine or a derivative thereof of formula II 5 wherein R1 and R2, which they can be the same or different, each one represents an atom of hydrogen or an acyl group, such as a lower alkanoyl group, as p. ex. an acetyl group or a straight chain aryl group or branched, as p. ex. methyl, ethyl, propyl or isopropyl; R 3 is an alkyl, alkenyl or alkaryl group straight or branched chain that is optionally substituted by a halogen atom or a cycloalkyl, hydroxy, alkoxy group, nitro, amino, aminoalkyl, acylamino, heteroaryl, heteroarylalkyl, aroyl, aroylalkyl or cyano; Y R 4 represents a hydrogen atom or of halogen attached to at least one of the cyclic carbons of the skeleton tetracyclic; and pharmaceutically acceptable salts of themselves, such as those consisting of hydrobromide, hydrochloride, methylsulfate or metaiodide in the manufacture of a medicine to combat inattention disorders 3. Use of galantamine or a salt thereof in the manufacture of a medicine to combat lack disorders of attention. 4. Use as claimed in any of the claims 1 to 3, wherein the disorder is a disorder of lack of attention with hyperactivity. 5. Use as claimed in any of the claims 1 to 3, wherein the disorder is a disorder hyperkinetic